PROJECT SUMMARY Heart failure (HF) is a growing, morbid, and costly public health problem. Consequently, there is increasing realization for the importance of early detection and prevention. Preliminary data suggests a meta-organismal pathway involving formation of trimethylamine N-oxide (TMAO) is a direct contributor to heart failure susceptibility and adverse prognosis. The novel pathway involves a complex interplay between chronic dietary exposure of specific dietary nutrients, gut microbe metabolism of these nutrients using specific microbial enzymes, and then host hepatic metabolism of the microbial waste product, ultimately producing a biologically active compound, TMAO. Preliminary studies show TMAO adversely influences myocardial function and promotes both myocardial fibrosis and heart failure phenotype. We propose to examine the role of specific chronic dietary exposures alternative to sodium in risk for adverse cardiac remodeling and heart failure, and to understand their potential mechanistic underpinnings. We will examine the role of gut microbes in heart failure susceptibility, and specific microbial enzyme systems in this process. Finally, we will explore the potential efficacy of therapeutic dietary approaches targeting this pathway for the prevention and treatment of heart failure. Successful completion of the proposed studies should provide both important mechanistic insights into a new pathway that contributes to heart failure development and progression, as well as develop novel diagnostic tests and therapeutic approaches for the treatment of heart failure.